Prevalence and Clinical Features of Takotsubo Cardiomyopathy in Taiwanese Patients Presenting with Acute Coronary Syndrome

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1 Original Article Takotsubo Cardiomyopathy in Taiwan Acta Cardiol Sin 2010;26:12 8 Coronary Heart Disease Prevalence and Clinical Features of Takotsubo Cardiomyopathy in Taiwanese Patients Presenting with Acute Coronary Syndrome Chen-Tung Hsu, 1 Cheng-Yun Chen, 1 Rei-Yeuh Chang, 1,2 Yung-Ping Chen, 1 I-Tseng Chu, 1 Hsin-Li Liang 1 and Cheng-Kang Chen 1 Background: Takotsubo cardiomyopathy (TCM), which has similar manifestations to acute coronary syndrome (ACS), was originally described in Japanese populations and has since been reported worldwide. However, sufficient epidemiological data from other Asian populations is lacking. The aim of this study was to evaluate the incidence of TCM and associated clinical features in patients presenting with ACS to a community hospital in southern Taiwan. Methods: Cases of 1338 patients who underwent coronary angiography for ACS between January 2003 and January 2009 were reviewed to identify TCM. Demographic characteristics, clinical histories, presenting symptoms, laboratory data, and electrocardiographic, echocardiographic and angiographic findings were noted. Results: Twelve patients met the criteria for clinical diagnosis of TCM (0.9%). All except for one were postmenopausal women. The initial presentation was chest pain in 8 patients. Seven patients developed symptoms after physical stress. Although ST-segment elevation was observed in 9 patients (75%) upon initial electrocardiography, all developed T-wave inversion. Nine patients presented with a typical pattern of apical ballooning, whereas 3 presented with atypical midventricular ballooning. All patients recovered from wall motion abnormalities, and the mean left ventricular ejection fraction increased from 41 10% to 67 6%. Six patients experienced complications such as pulmonary edema or ventricular tachycardia during acute phase; however there were no deaths during hospitalization or follow-up. Conclusion: The prevalence of TCM in our cohort of Taiwanese patients presenting with ACS was 0.9%. The prevalence was markedly higher in women. TCM should be included in the differential diagnosis of ACS, especially in postmenopausal woman following a stressful trigger. Key Words: Acute coronary syndrome Takotsubo cardiomyopathy Transient left ventricular apical ballooning Taiwan INTRODUCTION Received: November 1, 2009 Accepted: February 9, Division of Cardiology, Department of Medicine, Chia-Yi Christian Hospital; 2 Graduate Institute of Nature Hearing Sciences, Nanhua University, Chia-Yi, Taiwan. Address correspondence and reprint requests to: Dr. Cheng-Kang Chen, Division of Cardiology, Department of Medicine, Chia-Yi Christian Hospital, No. 539, Jung-Shiau Road, Chia-Yi 600, Taiwan. Tel: ext. 7354; Fax: ext. 5023; @cych.org.tw Takotsubo cardiomyopathy (TCM), also known as transient left ventricular (LV) apical ballooning syndrome, is a relatively recently described entity characterized by chest symptoms associated with electrocardiographic (ECG) changes (ST elevation or T-wave inversion) and mild elevation of cardiac enzymes. 1 The clinical presentation of TCM is very similar to that of acute coronary syndrome (ACS), however these patients do Acta Cardiol Sin 2010;26:

2 Takotsubo Cardiomyopathy in Taiwan not have significant coronary arterial stenosis or thombosis. 1 Typically, transient LV dysfunction may be present, with akinesis or hypokinesis of the mid-to-distal portion of the left ventricular chamber and hyperkinesis of the basal segments. Given the similarities in presentation, the potential exists for misdiagnosing TCM as ACS. Since the initial recognition and description of TCM in the Japanese population, the syndrome has now been reported worldwide. 2-4 However, TCM has been rarely reported in Taiwan. 5-8 Indeed, epidemiological data on the incidence of TCM in the Taiwanese population is yet to be reported. Therefore, the aim of this study was to evaluate the incidence of TCM as well as the associated clinical features in a community hospital in southern Taiwan. Given the already noted similarities between TCM and ACS, we specifically examined the records of patients presenting with ACS to ascertain TCM occurrence. METHODS Between January 2003 and January 2009, we retrospectively reviewed the records of all consecutive patients who underwent coronary angiography in our hospital with a presumed diagnosis of ACS. The inclusion criteria of acute coronary syndrome were: (1) unstable angina with ST depression of at least 1 mm or T-wave inversion with normal enzymes; (2) acute myocardial infarction without ST elevation; and (3) acute myocardial infarction with ST elevation. The exclusion criteria were: (1) suspected or proven acute myocarditis; (2) suspected or proven non-cardiac pathology (such as pheochromocytoma crisis, pulmonary embolism or aortic dissection). TCM was identified in these patients according to the following modified Mayo Clinic Criteria for the clinical diagnosis of TCM: 1 (1) transient hypokinesis, akinesis, or dyskinesis of the LV and mid segments with or without apical involvement and with regional wall motion abnormalities extending beyond a single epicardial vascular distribution; (2) absence of significant coronary stenosis (more than 50% of the luminal diameter) or angiographic evidence of acute plaque rupture; (3) new ECG abnormalities (ST-segment elevation and/or T-wave inversion); and (4) absence of pheochromocytoma or myocarditis. Demographic characteristics, clinical histories, preceding stressors, presenting symptoms, laboratory data, ECG, echocardiographic and angiographic findings were collected from review of patient medical records. Survival follow-up data were prospectively collected through clinical outpatient visits or telephone calls to patients or relatives. Major clinical events were cardiac death and rehospitalization due to recurrence of this syndrome. This study protocol was approved by our hospital s committee on ethics. Statistical analysis All data were analyzed using SPSS version 10.0 statistical software (SPSS Inc, Chicago, IL, USA). Continuous variables are presented as mean standard deviation and range. Categorical data are presented as absolute values and percentages. Changes in LV ejection fraction between initial presentation and follow-up were analyzed by paired t-test. A P value of < 0.05 was considered to be of statistical significance. RESULTS Among the 1338 patients with suspected ACS, 385 (28.8%) were women. Twelve patients met the diagnostic criteria for TCM, giving a prevalence of 0.9%. Of these patients, 11 were postmenopausal females; hence prevalence of TCM in females was much higher at 2.9%. The baseline characteristics of each patient are summarized in Table 1. The mean age of the TCM patient cohort was 72 10years(range:55to90years).Inmost cases, the initial presentation was chest pain, followed by dyspnea and syncope. Hypertension was by far the most common comorbidity, followed by diabetes mellitus and hypercholesterolemia. Seven of the 12 patients developed symptoms after physical stress, including acute medical illness, invasive procedures or surgery. There were no instances of preceding strong emotional stress. Six patients experienced complications, either pulmonary edema or ventricular tachycardia. The initial ECG showed sinus rhythm in 9 patients; two patients had chronic complete atrioventricular block, while one had chronic atrial fibrillation. ST-segment elevation was apparent in 9 patients (75%) upon initial ECG; however this resolved in all within a few days (Table 2). All of these patients developed T-wave inver- 13 Acta Cardiol Sin 2010;26:12 8

3 Chen-Tung Hsu et al. Table 1. Clinical characteristics of 12 patients with takotsubo cardiomyopathy No. Age Sex Comorbidity Presenting symptom Stressful event Complications 1 90 F Chronic CAVB Syncope None VT 2 77 F HTN, chronic CAVB Dyspnea Pacemaker implantation VT, pulmonary edema 3 71 F DM, HTN Chest pain Colonoscopy None 4 77 F HTN, old stroke Dyspnea Urosepsis Pulmonary edema 5 63 M Uremia, HTN Chest pain Lumbar osteomyelitis Pulmonary edema 6 65 F HTN, AF Chest pain None None 7 70 F DM, HTN, hypercholesterolemia Chest pain Gastrointestinal upset Pulmonary edema 8 70 F DM, HTN, hypercholesterolemia Chest pain None None 9 82 F Hypercholesterolemia Chest pain None None F None Syncope Hemorrhoidectomy VT, pulmonary edema F HTN, asthma Chest pain Acute bronchial asthma None F HTN Chest pain None None AF, atrial fibrillation; CAVB, complete atrioventricular block; DM, type 2 diabetes mellitus; HTN, Hypertension; VT, ventricular tachycardia. Table 2. Electrocardiographic changes and cardiac enzyme levels No. ST segment elevation T wave inversion Maximum QTc (ms) Peak CK/CK-MB (IU/L) Peak troponin I (ng/ml) 1 - V2-V5, II, III, avf / V1-V / V1-V4 V1-V / V3-V6, I, avl V5, V / V3-V4 V2-V6, I, II, avl / V2-V5 V3-V6 471~ / V2-V5 V2-V6, I, II, III, avf / V1-V4, I, avl / V3-V6, II, III, avf V2-V / V3-V6, II, III, avf V3-V6, I, II, III, avf / V2-V3 V2-V6, I, avl / V4-V6 V2-V5, II, III, avf / CK, creatine kinase; CK-MB, creatine kinase-mb fraction. sion. Q-waves were not apparent in any of our patients. The maximum corrected QT interval calculated using Bazett s formula was prolonged (> 450 milliseconds) in all but one patient. Representative electrocardiograms are shown in Figure 1. The mean peak creatine kinase and creatine kinase- MB levels were IU/L and IU/L, respectively (range: 98 to 704 IU/L and 15.4 to 82.6 IU/L). Troponin I levels (normal < 0.5 ng/ml) were elevated in 11 (92%) of the patients, with the mean peak level being ng/ml (range: 0.17 to ng/ml). Coronary angiography was performed less than 48 hours after symptom onset in all patients. Six patients (50%) had normal coronary arteries, and 6 patients (50%) had insignificant stenosis of any coronary artery. We observed one (8%) instance of transient vasospasm in the right coronary artery; this patient was treated with intracoronary nitrate injection. Four patients (33%) had a long wrap-around left anterior descending coronary artery (Table 3). Angiographic evidence of plaque rupture, or intracoronary thrombus formation was not observed in any of our patients. No provocation tests or endomyocardial biopsies were performed. All patients underwent concomitant LV angiography to assess the LV wall motion abnormality after coronary angiography. None of our patients Acta Cardiol Sin 2010;26:

4 Takotsubo Cardiomyopathy in Taiwan A B Figure 1. Typical electrocardiogram (ECG) changes in a woman with takotsubo cardiomyopathy. (A) Initial ECG shows mild ST-segment elevation with loss of R-wave progression in leads V2 and V3. (B) Evolution of symmetric T-wave inversion and QT prolongation on day 2. Echocardiogram studies were performed in a standard fashion to assess LV wall motion abnormality at presentation and follow-up in all patients. The LV ejection fraction was measured by modified Simpson s method. All patients recovered from wall motion abnormalities, with the mean LV ejection fraction increasing from 41 ± 10% upon admission to 67 ± 6% at follow-up (P < underwent follow-up LV angiography. Nine patients presented with a typical pattern of TCM, i.e. akinesis or hypokinesis of the mid-to-distal portion of the LV chamber (Table 3). Three patients presented with atypical midventricular ballooning without involvement of the LV apex. Representative left ventriculography images can be seen in Figure Acta Cardiol Sin 2010;26:12-8

5 Chen-Tung Hsu et al. Table 3. Echocardiographic and angiographic characteristics No. Apical or midventricular ballooning LVEF on admission, % Follow-up LVEF, % Long wrap-around LAD 1 A A M A A A A M A M A A A, apical ballooning; LAD, left anterior descending artery; LVEF, left ventricular ejection fraction; M, midventricular ballooning. LVEF was determined by echocardiography , Table 3). No pressure gradients or instances of LV outlet obstruction were observed. Five patients developed acute pulmonary edema requiring diuretics and ventilator support (in 4 patients). One patient (patient No. 2) required an intra-aortic balloon pump for treatment of unstable hemodynamics. Three patients developed ventricular tachycardia and 2 patients required electrical cardioversion. Initially, most patients were treated for ACS with pharmaceuticals including nitrates, -blockers, aspirin, clopidogrel, and heparin unless they had contraindications to these medications. Two patients also received a glycoprotein IIb/IIIa inhibitor (patients No. 6 and No. 9). Patients were discharged on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (n = 7), beta-blockers (n = 3), calcium channel blockers (n = 5), nitrates (n = 7), and antiplatelet agents (n = 8). No recurrence of symptoms or major adverse cardiac events occurred during follow-up ( months). A C Figure 2. Left ventriculography shows typical apical ballooning (A: end-diastole and B: end-systole). Left ventriculography (C: end-diastole and D: end-systole) shows an example of an atypical form of takotsubo cardiomyopathy with midventricular ballooning. B D DISCUSSION We found that the incidence of TCM was 0.9% in all patients taken to the catheterization laboratory under suspicion of ACS. The prevalence was higher in women, witharateof2.9%. The prevalence of TCM determined in this study is without doubt an underestimation of TCM in patients overall, given that we only assessed the records of patients undergoing coronary angiography and did not include patients in medical and surgical intensive care units where the syndrome is common but often unrecognized or misdiagnosed. Indeed, this assertion is sup- Acta Cardiol Sin 2010;26:

6 Takotsubo Cardiomyopathy in Taiwan ported by a prospective study where it was found that 28% of 92 consecutive patients admitted to the medical intensive care unit with acute medical illness developed echocardiographic evidence of LV apical ballooning. 9 Although TCM has been reported in both genders, 9 a review of the published literature indicates that the majority of cases ( 90%) are in women. 10,11 In keeping with these findings, the majority of patients with TCM in the present study were postmenopausal women. However, Fang and colleagues published data on ten patients with TCM showing a male predominance (six patients were men). 5 The male predominance could be accounted for by the retrospective and observational nature of the study. Further study in Taiwanese population is needed to clarify this issue. Several reports have suggested that wall motion abnormalities associated with TCM might not exclusively be located in apical segments, but may also occur in midventricular segments of the LV In the present study, we identified three patients with midventricular ballooning, accounting for 25% of patients with TCM. Although speculative, the atypical form with midventricular ballooning might reflect individual variations in the pattern of sympathetic innervation or the response to sympathetic stimulation. Kurowski and colleagues reported that transient midventricular LV ballooning was observed in 40% of patients with transient LV dysfunction; no differences in demographic, clinical, angiographic, laboratory parameters, or outcome were found between these patients and patients with apical ballooning. 12 However, Hahn et al. reported that patients with non-apical LV ballooning shared the same clinical features as those with the typical form of apical ballooning, but tended to be younger and have a lower incidence of cardiogenic shock, pulmonary edema and T-wave inversion. 13 The pathophysiology of TCM is not well understood. Several mechanisms for the reversible cardiomyopathy have been proposed, including catecholamineinduced myocardial stunning, multivessel epicardial spasm, microvascular dysfunction, acute myocarditis, and plaque rupture followed by spontaneous thrombolysis in a long wrap-around left anterior descending coronary artery. Spontaneously-aborted myocardial infarction in the territory of a long wrap-around left anterior descending coronary artery has also been proposed as a pathophysiological mechanism of TCM. 15 Ibanez and colleagues published data on five patients showing the presence of disrupted plaques in the middle-portion of the left anterior descending artery by intravascular ultrasound that was not visible on coronary angiography. 16 Myocardial stunning resulting from plaque rupture followed by spontaneous thrombolysis in a long wraparound left anterior descending coronary artery that supplies an extensive portion of the diaphragmatic LV would explain the peculiar wall motion abnormalities in the typical form of TCM. However, this mechanism is unlikely to account for the pathophysiology in most cases. In our study, only 4 patients had a long wraparound left anterior descending coronary artery. Moreover, the atypical form of TCM with midventricular ballooning would argue against this mechanism. Due to its clinical characteristics, TCM is frequently misdiagnosed as ACS, or ST-segment elevation myocardial infarction. The diagnosis of TCM is usually confirmed when coronary angiography is normal or reveals mild abnormalities. The characteristic ECG features of this syndrome are non-specific and include dynamic ST-segment elevation (< 2 mm) and/or T-wave inversion with prolongation of the QT interval in the anterior leads, as seen in our patients. Since the ECG and symptoms cannot reliably distinguish TCM from ACS, identification of TCM requires diligence on the part of the diagnosing physician and sound clinical judgment. If TCM is suspected, fibrinolytic therapy should be avoided and emergency coronary angiography should be performed in any patient presenting with ST-segment elevation. At the present time, there have been no controlled studies to guide clinical management of TCM; however it is reasonable to treat these patients with standard medications for LV systolic dysfunction during the acute phase. Appropriate medications include aspirin, betablockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics. Short-term anticoagulants may be helpful for the prevention of mural thrombus formation during LV dysfunction. Since LV dysfunction is transient and reversible in patients with TCM, the appropriate duration of therapy is not known. The authors of a multicenter, retrospective study report concluded that chronic treatment with beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers and aspirin did not seem to provide any benefit to patients with TCM. 17 A large-scale prospective trial is 17 Acta Cardiol Sin 2010;26:12 8

7 Chen-Tung Hsu et al. needed to determine the optimal strategies for acute and chronic management of TCM. In our study, six (50%) patients experienced complications, such as pulmonary edema or ventricular tachycardia, during the acute phase. However, supportive therapy according to the patient s hemodynamic status invariably led to spontaneous recovery. No patient died either during hospitalization or follow-up. In accordance with published research, 11 our findings indicate that patients are highly likely to have a favorable outcome once they have recovered from the acute stage of TCM. STUDY LIMITATIONS The present study has some limitations that should be acknowledged. Firstly, evaluations of TCM were performed at a single institution. Secondly, the study was retrospective and observational in nature. Clinical data were collected from review of patient medical records and we did not routinely perform examinations to exclude pheochromocytoma. Furthermore, echocardiographic examinations and outpatient visits were not scheduled during follow-up; hence we could not precisely assess the time course of normalization of LV dysfunction. Moreover, we did not perform systemic investigation on the possible etiologic mechanisms such as catecholamine measurements, magnetic resonance imaging, viral antibody titer, or pathology. Further study is needed to elucidate the pathophysiology of this syndrome. CONCLUSION In conclusion, TCM is a clinical entity with a typical or atypical form of transient LV dysfunction, a clinical presentation mimicking ACS and a favorable outcome. The incidence was 0.9% in our population of Taiwanese patients presenting with symptoms of ACS. The prevalence was higher (2.9%) in women than in men. TCM should be included in the differential diagnosis of patients presenting with ACS, especially in postmenopausal women following a stressful trigger. REFERENCES 1. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155: Desmet WJ, Adriaenssens BF, Dens JA. Apical ballooning of the left ventricle: first series in white patients. Heart 2003;89: Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005;111: Abdulla I, Kay S, Mussap C, et al. Apical sparing in tako-tsubo cardiomyopathy. Intern Med J 2006;36: Fang CC, Jao YT, Yi C, et al. Transient left ventricular apical ballooning syndrome: the first series in Taiwanese patients. Angiology 2008;59: Lin PC, Chang CJ, Wang CL, Kuo CT. Reversible left ventricular dysfunction with apical ballooning: a case report of ampulla cardiomyopathy. Acta Cardiol Sin 2005;21: Chen CK, Chen CY. Atypical takotsubo cardiomyopathy (transient left mid ventricular ballooning syndrome). Acta Cardiol Sin 2007;24: Chang NC, Kawai S. Takotsubo (ampulla) cardiomyopathy is not rare in Taiwan. Acta Cardiol Sin 2009;25: Park JH, Kang SJ, Song JK, et al. Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest 2005;128: Donohue D, Movahed MR. Clinical characteristics, demographics and prognosis of transient left ventricular apical ballooning syndrome. Heart Fail Rev 2005;10: Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2008;124: Kurowski V, Kaiser A, von HK, et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132: Hahn JY, Gwon HC, Park SW, et al. The clinical features of transient left ventricular nonapical ballooning syndrome: comparison with apical ballooning syndrome. Am Heart J 2007;154: Hurst RT, Askew JW, Reuss CS, et al. Transient midventricular ballooning syndrome: a new variant. J Am Coll Cardiol 2006; 48: Ibanez B, ezet-mazuecos J, Navarro F, et al. Takotsubo syndrome: a Bayesian approach to interpreting its pathogenesis. Mayo Clin Proc 2006;81: Ibanez B, Navarro F, Cordoba M, et al. Tako-tsubo transient left ventricular apical ballooning: Is intravascular ultrasound the key to resolve the enigma? Heart 2005;91: Fazio G, Pizzuto C, Barbaro G, et al. Chronic pharmacological treatment in takotsubo cardiomyopathy. Int J Cardiol 2008;127: Acta Cardiol Sin 2010;26: